Deletion of the Collagen-specific Molecular Chaperone Hsp47 Causes Endoplasmic Reticulum Stress-mediated Apoptosis of Hepatic Stellate Cells

Kawasaki, Kunito; Ushioda, Ryo; Ito, Shinya; Ikeda, Kazuo; Masago, Yusaku; Nagata, Kazuhiro

doi:10.1074/jbc.m114.592139

Cited by 75 publications

(61 citation statements)

References 50 publications

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“…One mechanism by which this can occur is HSC apoptosis . Induced nonphysiological ER stress in HSCs was shown to be antifibrotic, attributed to induction of cell death in cultured HSCs . We observed increased UPR signaling in siTANGO1 cells, and increased expression of CHOP and DR5, genes involved in UPR‐mediated apoptosis.…”

Section: Discussionmentioning

confidence: 72%

The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice

et al. 2016

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Background/Aims Fibrogenesis encompasses the deposition of matrix proteins such as collagen I by hepatic stellate cells (HSCs) that culminates in cirrhosis. Fibrogenic signals drive transcription of procollagen I, which enters the endoplasmic reticulum (ER), is trafficked through the secretory pathway, and released to generate extracellular matrix. Alternatively, disruption of procollagen I ER export could activate the unfolded protein response (UPR) and drive HSC apoptosis. Using a siRNA screen, we identified TANGO1 as a potential player in collagen I secretion. We investigated the role of TANGO1 in procollagen I secretion in HSCs and liver fibrogenesis. Methods/Results Depletion of TANGO1 in HSCs blocked collagen I secretion without affecting other matrix proteins. Disruption of secretion led to procollagen I retention within the ER, induction of the UPR, and HSC apoptosis. In wild-type HSCs, both TANGO1 and the UPR were induced by TGFβ. As the UPR upregulates proteins involved in secretion, we studied whether TANGO1 was a target of the UPR. We found that UPR signaling is responsible for upregulating TANGO1 in response to TGFβ, and this mechanism is mediated by the transcription factor XBP1. In vivo, murine and human cirrhotic tissue displayed increased TANGO1 mRNA levels. Finally, TANGO1+/− mice displayed less hepatic fibrosis compared to wild-type mice in two separate murine models: CCl4 and BDL. Conclusion Loss of TANGO1 leads to procollagen I retention in the ER which promotes UPR-mediated HSC apoptosis. TANGO1 regulation during HSC activation occurs through a UPR dependent mechanism that requires the transcription factor XBP-1. Finally, TANGO1 is critical for fibrogenesis through mediating HSC homeostasis. Our work reveals a unique role for TANGO1 and the UPR in facilitating collagen I secretion and fibrogenesis.

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Section: Discussionmentioning

confidence: 72%

The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice

et al. 2016

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“…This work builds upon previous efforts to recreate chronic ER stress in fish larvae (Cinaroglu et al, 2011), and to elicit chronic ER stress in mammals by overexpression of misfolded ER client proteins or deletion of ER chaperones (e.g., [Ji et al, 2011; Zode et al, 2011; Kawasaki et al, 2015]). We have used this system as a tool to probe how UPR signaling becomes altered during persistent and/or repeated activation.…”

Section: Discussionmentioning

confidence: 99%

Experimental reconstitution of chronic ER stress in the liver reveals feedback suppression of BiP mRNA expression

Gomez

Rutkowski

2016

eLife

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Endoplasmic reticulum (ER) stress is implicated in many chronic diseases, but very little is known about how the unfolded protein response (UPR) responds to persistent ER stress in vivo. Here, we experimentally reconstituted chronic ER stress in the mouse liver, using repeated injection of a low dose of the ER stressor tunicamycin. Paradoxically, this treatment led to feedback-mediated suppression of a select group of mRNAs, including those encoding the ER chaperones BiP and GRP94. This suppression was due to both silencing of the ATF6α pathway of UPR-dependent transcription and enhancement of mRNA degradation, possibly via regulated IRE1-dependent decay (RIDD). The suppression of mRNA encoding BiP was phenocopied by ectopic overexpression of BiP protein, and was also observed in obese mice. Our findings suggest that persistent cycles of UPR activation and deactivation create an altered, quasi-stable setpoint for UPR-dependent transcriptional regulation—an outcome that could be relevant to conditions such as metabolic syndrome.DOI: http://dx.doi.org/10.7554/eLife.20390.001

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“…These observations indicated that HSP47 may be a potential therapeutic target in LSCC and indirectly supported the concept that low HSP47 expression is correlated with short survival and poor prognosis in LSCC. As shown in previous studies, HSP47 plays an important regulatory role in various types of tumours (39)(40)(41) and has a close relationship with tumour apoptosis (40,42). However, the mechanism of HSP47-mediated Hep-2 cell apoptosis is still unknown.…”

Section: Discussionmentioning

confidence: 99%

HSP47 is associated with the prognosis of laryngeal squamous cell carcinoma by inhibiting cell viability and invasion and promoting apoptosis

et al. 2017

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Abstract. Heat shock protein 47 (HSP47) is a 47 kDa collagen binding protein that has a close relationship with the development and progression of tumours. However, little is known concerning the expression profile of HSP47 in laryngeal squamous cell carcinoma (LSCC) patients and there is still insufficient data concerning the underlying mechanisms. The aim of the present study was to explore the expression of HSP47 in LSCC and provide an overview of its association with tumourigenicity and clinical prognosis. The expression of HSP47 in LSCC and adjacent non-cancerous laryngeal tissues was assessed via western blotting and immunohistochemical studies. The prognostic significance of HSP47 expression was analysed using a Kaplan-Meier survival curve. To investigate the influence of HSP47 on the viability, invasion and apoptosis of a LSCC cell line, we performed an in vitro analysis with plasmid vectors and small interfering RNA (siRNA). Our results showed that HSP47 protein expression in the LSCC tissues was markedly decreased compared to that noted in the adjacent non-cancerous tissues, and low expression of HSP47 was correlated with poor prognosis in LSCC patients. Upregulation of HSP47 via plasmid vectors inhibited the proliferation, reduced the invasive ability, increased the sensitivity to cisplatin chemotherapy, promoted apoptosis, and induced the G1 phase arrest of LSCC cells in vitro. The expression of apoptosis-regulating proteins was also altered when HSP47 was upregulated, involving increased expression of cleaved caspase-7/-8/-9, PARP, and Bax and decreased expression of Bcl-2. Our present data suggest that HSP47 is an important prognostic factor and an attractive therapeutic target in LSCC due to its influence on the biological behaviour of LSCC cells.

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Deletion of the Collagen-specific Molecular Chaperone Hsp47 Causes Endoplasmic Reticulum Stress-mediated Apoptosis of Hepatic Stellate Cells

Cited by 75 publications

References 50 publications

The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice

The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice

Experimental reconstitution of chronic ER stress in the liver reveals feedback suppression of BiP mRNA expression

HSP47 is associated with the prognosis of laryngeal squamous cell carcinoma by inhibiting cell viability and invasion and promoting apoptosis

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